NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 3, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001852299.8

Allele description [Variation Report for NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu)]

NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu)

Other names:

p.R174L:CGC>CTC

HGVS:

NC_000011.10:g.2570671G>T
NG_008935.1:g.130681G>T
NM_000218.3:c.521G>TMANE SELECT
NM_001406836.1:c.521G>T
NM_001406837.1:c.251G>T
NM_181798.2:c.140G>T
NP_000209.2:p.Arg174Leu
NP_000209.2:p.Arg174Leu
NP_001393765.1:p.Arg174Leu
NP_001393766.1:p.Arg84Leu
NP_861463.1:p.Arg47Leu
NP_861463.1:p.Arg47Leu
LRG_287t1:c.521G>T
LRG_287t2:c.140G>T
LRG_287:g.130681G>T
LRG_287p1:p.Arg174Leu
LRG_287p2:p.Arg47Leu
NC_000011.9:g.2591901G>T
NM_000218.2:c.521G>T
NM_181798.1:c.140G>T
NR_040711.2:n.414G>T

Protein change:

R174L

Links:

dbSNP: rs199472697

NCBI 1000 Genomes Browser:

rs199472697

Molecular consequence:

NM_000218.3:c.521G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.521G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.251G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.140G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002308494	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 3, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21956039, 30571187, 9386136, 14998624, 23130128, 23392653, 29532034, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002308494

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 3, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype- and mutation site-specific QT adaptation during exercise, recovery, and postural changes in children with long-QT syndrome.

Aziz PF, Wieand TS, Ganley J, Henderson J, Patel AR, Iyer VR, Vogel RL, McBride M, Vetter VL, Shah MJ.

Circ Arrhythm Electrophysiol. 2011 Dec;4(6):867-73. doi: 10.1161/CIRCEP.111.963330. Epub 2011 Sep 28.

PubMed [citation]

PMID:: 21956039
PMCID:: PMC3247652

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.

Vanoye CG, Desai RR, Fabre KL, Gallagher SL, Potet F, DeKeyser JM, Macaya D, Meiler J, Sanders CR, George AL Jr.

Circ Genom Precis Med. 2018 Nov;11(11):e002345. doi: 10.1161/CIRCGEN.118.002345.

PubMed [citation]

PMID:: 30571187
PMCID:: PMC6309341

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002308494.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 174 of the KCNQ1 protein (p.Arg174Leu). This missense change has been observed in individual(s) with long-QT syndrome (PMID: 21956039). ClinVar contains an entry for this variant (Variation ID: 200814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 14998624, 23130128, 23392653, 29532034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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